1. Field of the Invention
The invention relates to methods of using interleukin-1 (IL-1) antagonists to treat autoinflammatory diseases, such as, for example, including familial mediterranean fever (FMF), NOMID/CINCA, Muckle-Wells Syndrome, FCAS, and tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS).
2. Description of Related Art
One important group of autoinflammatory disorders encompasses autosomal dominant conditions associated with mutations in CIAS-1, a gene that encodes a pyrin-related protein called “cryopyrin” (Feldmann et al. (2002) Am. J. Hum. Genet. 71:198-203; Hoffman et al. (2001) Nat. Genet. 29:301-305). These disorders include Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS). These disorders present a spectrum of clinical manifestations ranging from FCAS being the mildest to the seriously disabling disease of NOMID/CINCA. An urticaria-like skin rash is common to the entire spectrum of these diseases. In patients with FCAS, this rash is inducible by cold exposure while most patients with MWS or NOMID present with daily rashes that are consistently provoked by a number of different stimuli. Conjunctivitis is present in all forms of disease expression, however, hearing loss, aseptic meningitis and arthritis are mainly seen in patients with MWS and NOMID/CINCA. The disfiguring and disabling body overgrowth at the epiphyses and patellae is only seen in patients with NOMID/CINCA.
FMF is a recessively inherited condition characterized by episodes of fever and serositis or synovitis; some subjects also develop systemic amyloidosis (Balow et al. (1997) Genomics 44:280-291). The FMF gene encodes a novel protein called pyrin that is the prototype of a family of molecules involved in the regulation of apoptosis (cell-death) and inflammation. The precise biochemical mechanism by which these proteins function, and by which mutations cause disease, is still unknown.
Still's Disease (systemic onset juvenile idiopathic arthritis), is manifest by spiking fevers, evanescent salmon color rash, arthritis, arthralgia, and hepatosplenomegaly (Masson et al. (1995) Rev. Rhum. Engl. Ed. 62:748-757; Spiegel et al. (2000) Arthritis Rheum. 43:2402-2409). There are as yet no definitive genetic associations with Still's Disease and the pathogenesis is poorly understood. Interestingly, many of the signs and symptoms of Still's disease are similar to those with autoinflammatory disease. Still's Disease typically first occurs during childhood, but can also have its onset in adulthood.
Similarly, Kawasaki disease is a disease affecting children that is accompanied by fevers, swelling and arthritic joints, and rash, as well as vascular inflammation that can cause permanent coronary damage in approximately 15-25% of affected children. Two other similar diseases are Blau's syndrome and Early Onset Sarcoidosis (EOS), both of which are caused by a gain of function mutations in NOD2, a protein similar to Pyrin, and cause rash, granulomatosis, arthritis and uveitis. Other diseases that have also been considered autoinflammatory include, Hidradenitis suppurativa, Behcet's, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), and Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA syndrome).
The pathogenesis of autoinflammatory disease is not completely understood. There is a growing body of evidence that interleukin-1 (IL-1) plays a role in a number of these conditions and that targeting of this cytokine can provide important benefits (Hoffman et al. (2004) Arthritis. Rheum. 50:345-349). There is clearly a need to develop improved therapeutic treatment of these autoinflammatory diseases.